Manufacture of retinoids

ABSTRACT

A process for the manufacture of retinal (I) comprises reacting a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadiene derivative (IIa) or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-1,4-pentadiene derivative (IIb) or a 5-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-1-pentene derivative (IIc) or a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1-en-4-yne derivative (IId) or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-penta-1-en-4-yne derivative (IIe) with a 1,3-butadiene derivative H2C═C(CH3)CCH═CHOR4 (III) in the presence of a Lewis or Brönsted acid and subjecting the compound obtained in each case [(IVa), (IVb), (IVc), (IVd) or (IVe), respectively] to basic or acidic conditions to eliminate therefrom the moiety R2H and thus produce, according to the immediate precursor, retinal itself or a particular derivative thereof [(I′), (I″), (Va) or (Vb), respectively] and, where in two cases such derivative is produced featuring a triple bond [derivative (Va) or (Vb)], hydrogenating this to produce retinal (I) or the derivative (I′), respectively, and each case where a derivative (I′) or (I″) has been produced, isomerizing this under basic or acidic conditions or in the presence of a metal catalyst to the desired retinal (I). The so-produced retinal is usually in the form of an isomeric mixture, normally as (9 E/Z, 13 E/Z)-retinal, and this can be isomerized according to a further inventive aspect to (all-E)-retinal by the acid-catalyzed formation of an adduct of (all-E)-retinal with hydroquinone in crystalline form. The so obtained (all-E)-retinal-hydroquinone adduct can then if desired be converted to vitamin A alcohol in the predominantly (all-E)-isomeric form by a method known per se. The novel starting materials (IIa), (IIb), (IIc), (IVI) and (IIe) represent a still further inventive aspect. Retinal is a valuable intermediate in the synthesis of further vitamin A compounds (retinoids). The retinoids, particularly vitamin A alcohol (retinol), are known to be valuable substances which promote the well-being of humans, inter alia in respect of vision, the immune system and growth, and for this reason are often used as components of multivitamin preparations and as additives for certain food- and feedstuffs.

This application is the National Stage of International Application No.PCT/EP02/11878, filed Oct. 24, 2002.

The present invention is concerned with a process for the manufacture ofvitamin A aldehyde (retinal), a valuable intermediate in the synthesisof further vitamin A compounds (retinoids). The retinoids, particularlyvitamin A alcohol (retinol), are known to be valuable substances whichpromote the well-being of humans, inter alia in respect of vision, theimmune system and growth, and for this reason are often used ascomponents of multivitamin preparations and as additives for certainfood- and feedstuffs. The present invention further concerns novelstarting materials in the aforementioned process and further processsteps leading to (all-E)-vitamin A acetate.

According to the present invention there is provided a process for themanufacture of retinal, of the formula

which comprises reacting a5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadiene derivative of thegeneral formula

or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-1,4-pentadiene derivative ofthe general formula

or a 5-(2,6,6-trimethyl-2-cyclohexen-1-ylidene) 1-pentene derivative ofthe general formula

or a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1-en-4-yne derivative ofthe general formula

or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-penta-1-en-4-yne derivative ofthe general formula

wherein

-   R¹ signifies hydroxyl or a group OR³,-   R² signifies chlorine, bromine, C₁₋₆-alkoxy, C₁₋₆-alkylthio,    aryloxy, arylthio, (C₁₋₆-alkyl)-carbonyloxy, aroyloxy,    tri(C₁₋₆-alkyl)silyloxy, di(C₁₋₆-alkyl)phosphonyloxy,    (C₁₋₆-alkyl)sulphonyloxy, arylsulphonyloxy, (C₁₋₆-alkyl)sulphonyl,    arylsulphonyl, di(C₁₋₆-alkyl)amino, N-aryl-(C₁₋₆-alkyl)amino or    diarylamino, and-   R³ signifies C₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl, aroyl,    (C₁₋₆-alkoxy)carbonyl, tri-(C₁₋₆-alkyl)silyl,    di(C₁₋₆-alkyl)phosphonyl, diarylphosphonyl, (C₁₋₆-alkyl)sulphonyl or    arylsulphonyl, with a 1,3-butadiene derivative of the general    formula

wherein R⁴ signifies C₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl ortri(C₁₋₆-alkyl)silyl, in the presence of a Lewis or Brönsted acid andsubjecting the so-obtained compound of the general formula

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIa) or

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIb) or

(starting from the 5-substituted 1-pentene derivative of the formulaIIc) or

(starting from the 5-substituted penta-1-en-4-yne derivative of theformula IId) or

(starting from the 5-substituted penta-1-en-4-yne derivative of theformula IIe)to basic or acidic conditions to eliminate therefrom the moiety R²H andthus produce, from the compound of the formula IVa, retinal of theformula I, or, from the compound of the formula IVb, the compound of theformula

or, from the compound of the formula IVc, the compound of the formula

or, from the compound of the formula IVd, the compound of the formula

or, from the compound of the formula IVe, the compound of the formula

and, where a compound of the formula Va or Vb has been produced,hydrogenating this to produce retinal of the formula I or the compoundof the formula I′ respectively, and in each case where a compound of theformula I′ or I″ has been produced, isomerizing this under basic oracidic conditions or in the presence of a metal catalyst to the desiredretinal of the formula I.

In the above definition the term “C₁₋₆-alkyl” embraces (from C₃)straight-chain or branched alkyl groups with up to six carbon atoms,such as methyl, ethyl, isopropyl, tert. butyl, neopentyl and n-hexyl.This applies equally to the C₁₋₆-alkyl part of such groups as“C₁₋₆-alkoxy” and “C₁₋₆-alkylthio”, and to all the bracketed C₁₋₆-alkyland C₁₋₆-alkoxy groups. Where more than one C₁₋₆-alkyl group is presentin a group signified by R², R³ or R⁴, e.g. in such groups as“tri(C₁₋₆-alkyl)silyloxy”, di(C₁₋₆-alkyl)amino”,“di(C₁₋₆-alkyl)phosphonyl” or “tri(C₁₋₆-alkyl)silyl”, such C₁₋₆-alkylgroups may be the same or different. “Aryl” as such or as the aryl (or“ar”) part of “aryloxy”, “arylthio”, “aroyloxy”, “arylsulphonyloxy”,“arylsulphonyl”, “N-aryl-(C₁₋₆-alkyl)amino”, diarylamino”, “aroyl” or“diarylphosphonyl” means phenyl, 1-naphthyl or 2-naphthyl, or aconventionally substituted such group, e.g. p-tolyl.

The above formulae I, I′, I″, IIa, IIb, IIc, IId, IIe, III, IVa, IVb,IVc, IVd, IVe, Va and Vb embrace in each case isomeric forms, e.g.optically active or inactive and E/Z-isomers, as well as mixturesthereof, unless expressly stated to the contrary. With respect to theE/Z isomerism, although the (all-E) isomeric form of the intermediate ofthe formula IVa, IVb, IVc, IVd, IVe, Va, Vb, I′ or I″ and of theproduct, retinal, of the formula I, is in each case preferred, each isnormally present or produced, as appropriate, as a mixture of E- andZ-isomers.

In the first step of the process in accordance with the invention, i.e.the reaction of the derivative of the formula Ia, IIb, IIc, IId or IIe[hereinafter referred to for brevity as the “5-substituted pentadiene”,“pentadiene”, “pentene”, “penta-1-en-4-yne” or “penta-1-en-4-yne”derivative, respectively [or collectively as “5-substitutedpent(adi)en(yn)e”]with the 1,3-butadiene derivative under acidicconditions, an exclusive attack of the former derivative at theγ-position of the 1,3-butadiene derivative takes place.

This first process step is conveniently carried out by reacting the5-substituted pent(adi)en(yn)e derivative of the formula IIa, IIb, IIc,IId or IIe with the 1,3-butadiene derivative of the formula III in anorganic solvent at temperatures in the range of about −70° C. to about+60° C., preferably in the temperature range of about −30° C. to roomtemperature, and in the presence of a Lewis or Brönsted acid as thecatalyst. Suitable organic solvents are, in general, polar or non-polaraprotic solvents. Such solvents are, for example, lower halogenatedaliphatic hydrocarbons, e.g. methylene chloride and chloro-form; loweraliphatic and cyclic ethers, e.g. diethyl ether, tert, butyl methylether and tetrahydrofuran; lower aliphatic nitrites, e.g. acetonitrile;lower aliphatic esters, e.g. ethyl acetate; lower aliphatichydrocarbons, e.g. pentane and hexane; as well as aromatichydro-carbons, e.g. toluene. The preferred solvent is acetonitrile,optionally in combination with further aforementioned solvents. Where amixture of acetonitrile with a further solvent is used, the ratio byvolume of acetonitrile to such other solvent is preferably about 1:1 toabout 1:0.5. Examples of Lewis acids which can be used are zincchloride, zinc chloride dietherate, zinc bromide, zincdi(trifluoromethanesulphonate), titanium tetrachloride, tintetrachloride, boron trifluoride etherate, iron(III) chloride,trimethylsilyl triflate as well as lithium perchlorate, and examples ofBrönsted acids which can be used are p-toluene-sulphonic acid,methanesulphonic acid, trifluoromethanesulphonic acid, sulphuric acid aswell as trifluoroacetic acid. In general, the Lewis acids, especiallythe aforementioned zinc salts, boron trifluoride etherate and iron(III)chloride, are preferred. The acid catalysts are in general used incatalytic (below stoichiomeric) amounts, conveniently in an amount whichis 0.5 to 30 mmol percent based on the amount of 5-substitutedpent(adi)en(yn)e derivative used, the mol percent range preferably beingfrom about 1% to 15%. Where a 5-substituted pent(adi)en(yn)e derivativeof the formula, IIa, IIb, IIc, IId or IIe is used in which R² signifiesa basic group, in particular di(C₁₋₆-alkyl)amino,N-aryl-(C₁₋₆-alkyl)amino or diarylamino, a greater relative amount ofacid catalyst will clearly be required, generally at least one molequivalent. Furthermore, there are conveniently used 1.1 to 2.5equivalents, preferably 1.1 to 1.8 equivalents, of 1,3-butadienederivative per equivalent of 5-substituted pent(adi)en(yn)e derivative.Moreover, the reaction is conveniently effected at normal pressure. Ingeneral the pressure is not critical.

In preparing for the isolation of the product of the formula IVa, IVb,IVc, IVd or IVe, as appropriate, an acid, preferably slightly diluteaqueous acetic acid, for example featuring a ratio by volume aceticacid:water of about 9:1, may be added to the reaction mixture and themixture is subsequently stirred for a period, for example about 30minutes to about 2 hours, conveniently in the temperature range of about−10° C. to about 30° C. This incorporated acidification/hydrolysis stepensures that the desired intermediate of the formula IVa, IVb, IVc, IVdor IVe is finally produced from the reaction of the pent(adi)en(yn)ederivative of the formula Ia, IIb, IIc, IId or IIe with the1,3-butadiene derivative of the formula III. Theacidification/hydrolysis step is generally unnecessary, however, whenthe latter derivative features R⁴ as tri(C₁₋₆-alkyl)silyl. In any eventthe acidification/hydrolysis step is useful to remove excess butadienederivative from the mixture after reaction and before the isolation ofthe product of the formula IVa, IVb, IVc, IVd or IVe.

The product of the formula IVa, IVb, IVc, IVd or IVe can then beisolated from the reaction mixture and, if desired, purified in a mannerknown per se. Typically, the mixture is combined with water and thewhole is extracted with a water-immiscible organic solvent, such as, forexample, a lower alkane, dialkyl ether or aliphatic ester, e.g. hexane,tert. butyl methyl ether or, respectively, ethyl acetate, and theorganic phase is washed with water and/or sodium bicarbonate solutionand/or saturated aqueous sodium chloride solution, dried andconcentrated. The so-isolated and at least to some extent washed crudeproduct can then, if desired, be purified further, for example by columnchromatography, e.g. using silica as the stationary phase and an elutingagent such as hexane, ethyl acetate, toluene or a mixture of one or moreof these.

With respect to the further (second) process step, i.e. the eliminationof the compound R²H from the compound of the formula IVa, IVb, IVc, IVdor IVe, this can be effected with a base or an acid. Eliminations of thealkanol from β-alkoxyaldehydes or δ-alkoxy-α,β-unsaturated aldehydeswith the formation of the corresponding α,β-unsaturated aldehydes areknown in the chemical literature and can be carried out under a varietyof conditions, and such methodology can be applied to the present case.For example, in the field of known base-induced eliminations1,8-diazabicyclo[5.4.0]undec-7-ene is very often used as the base in anamount of about 1 to 2 equivalents per equivalent of aldehyde used. Suchconditions are used in the known production of carotenoids [see, interalia, Bull. Chem. Soc. Japan 50, 1161 et seq. (1977), ibid. 51, 2077 etseq. (1978), Chem. Lett. 1975, 1201 et seq. and GermanOffenlegungsschrift 2,701,489] and of vitamin A [see, inter alia, Chem.Lett. 1975, 1201 et seq. and J. Gen. Chem. USSR, 32, 63 et seq. (1962)].Further methodology, using a sodium alkanolate as the base, is describedin, for example, the European Patent Publications (EP) 814,078, 816,334and 978,508. As examples of acid-induced alkanol cleavages reference isagain made to Bull. Chem. Soc. Japan 50, 1161 et seq. (1977) and to J.Gen. Chem. USSR 30, 3875 et seq. (1960), in which p-toluene-sulphonicacid or 85% phosphoric acid is used as the acid catalyst. The buffersystem sodium acetate/acetic acid [Helv. Chem. Acta 39, 249 et seq. and463 et seq. (1956) and U.S. Pat. NoS. 2,827,481 and 2,827,482] has beenused for such a cleavage, especially in the production of carotenoids.In the case of corresponding alkoxy ketones (β-alkoxy-ketones orδ-alkoxy-α,β-unsaturated ketones), too, the cleavage of the alkanol ingeneral succeeds very well: see in this respect Synthesis 1986, 1004 etseq. or J. Org. Chem. 49, 3604 et seq. (1984). Taking into considerationthis and other pertinent literature a person skilled in the art willhave no difficulties in finding reaction conditions for the successfulperformance of the second step of the process in accordance with thepresent invention.

Furthermore, the elimination of the compound R²H can also be carried outwith several equivalent amounts of a base for each equivalent of thecompound of the formula IVa, IVb, IVc, IVd or IVe. Thus, the processstep in this case is conveniently carried out by submitting the compoundof the formula IVa, IVb, IVc, IVd or IVe, dissolved in a suitableorganic solvent, to treatment with a base with elimination of thecompound R²H. Suitable organic solvents are, in general, protic oraprotic solvents or mixtures thereof, such as, for example, alcohols,e.g. ethanol and isopropanol, and alcohol mixtures; lower halogenated,preferably chlorinated, aliphatic hydrocarbons, e.g. methylene chlorideand chloroform; and aromatic hydrocarbons, e.g. toluene. The base can beinorganic or organic, and these are suitably, in general, strong bases,especially those alkali metal alcoholates which are stronger bases, e.g.sodium ethylate, and nitrogen-containing bases, such as1,8-diaza-bicyclo[5.4.0]undec-7-ene, trialkylamines, e.g. triethylamine,and pyridine. As indicated above, there is conveniently used at leastone equivalent of base per equivalent of the compound of the formulaIVa, IVb, IVc, IVd or IVe, preferably about 1 to about 2 equivalents ofbase.

When an alkali metal alcoholate is used as the base, either a solutionof the sodium alkoxide in the alkanol is prepared in advance or thissolution is prepared freshly from metallic sodium and the alkanol. Thebringing together of the alkanolic solution of the sodium alkoxide withthe solution or suspension of the compound of the formula IVa, IVb, IVc,IVd or IVe in the (same) alkanol, preferably likewise prepared inadvance, can be effected in either sequence. The reaction mixture isthen stirred, suitably in the temperature range of about −20° C. toabout 120° C., preferably at temperatures of about 0° C. to about 70° C.Depending on the boiling point of the solvent the reaction isconveniently effected at normal pressure or with a slight excesspressure (In order to achieve the desired temperature). In general,however, the pressure is not critical. Under these conditions theelimination reaction is normally completed within a few hours,especially after about 30 minutes to about 4 hours.

In the case of an acid-induced elimination of the compound R²H, suitableacids are, in general, strong mineral acids, such as, for example,hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid andperchloric acid, and sulphonic acids, such as, for example,methanesulphonic acid, trifluoromethanesulphonic acid andp-toluenesulphonic acid. The mineral acids can be aqueous and, dependingon the acid, can have a concentration of about 10 to about 50%.Hydrochloric acid (especially about 10 to 37%), hydrobromic acid(especially about 25 to 63%) or hydriodic acid (e.g. 47%) is the mostsuitable. In this case only a catalytic amount, i.e. up to a maximum of1 equivalent per equivalent of the compound of the formula IVa, IVb,IVc, IVd or IVe, preferably about 0.1 to about 1 equivalent, isrequired. Further, the acid-induced elimination is effected in a solventin which the compound of the formula IVa, IVb) IVc, IVd or IVe has agood solubility and is dissolved therein (a so-called “homogeneouscleavage”) or in a solvent in which this is not the case, i.e. in whichthe compound of the formula IVa, IVb, IVc, IVd or IVe is instead insuspension (“heterogeneous cleavage”). In both cases, however, the acidcatalyst need not be completely dissolved. Suitable solvents for thehomogenous cleavage are especially halogenated aliphatic hydrocarbons,e.g. methylene chloride, chloroform and 1,2-dichloroethane, and aromatichydrocarbons, e.g. benzene and toluene. Suitable solvents (dispersionmedia) for the heterogeneous cleavage are lower aliphatic nitriles,ketones and carboxylic acids, e.g. acetonitrile, acetone and,respectively, acetic acid, preferably acetonitrile and acetone. In bothcases the elimination is conveniently effected in the temperature rangeof about −20° C. to about +50° C., preferably in the range of about 0°C. to room temperature. The reaction time depends in each case on thereaction temperature and can amount to several hours, the eliminationreaction normally being completed at the latest after about 5 hours.

Irrespective of the chosen procedure for the R²H elimination step, theproduct of the formula I, I′, I″, Va or Vb, as appropriate, can beisolated from the reaction mixture in a manner known per se, normally bycooling the reaction mixture, conveniently to room temperature or evento about 0° C., optional addition of water and extraction with awater-immiscible organic solvent. As such a solvent there is suitablyused a lower aliphatic hydrocarbon, e.g. pentane or hexane; an aromatichydrocarbon, e.g. toluene; or a lower aliphatic ester, e.g. ethylacetate. After its isolation the product can be purified further, ifnecessary or desired, by column chromatography or another conventionalmethod for purifying retinal or an isomer or derivative thereof.

In the case where the one starting material of the process of thepresent invention is the 5-substituted penta-1-en-4-yne derivative ofthe formula IId or IIe, the product at this stage of the process, i.e.after the elimination of the moiety R²H from the compound of the formulaIVd or IVe, as appropriate, is the compound of the formula Va or Vb,respectively. The next stage is the hydrogenation to produce retinal orthe compound of the formula I′, respectively. Said hydrogenation can beeffected under catalytic hydrogenation conditions known per se, e.g.those conditions used in the analogous procedures described inHouben-Weyl, Methoden der organischen Chemie, Vol. IV/1c (“Reduktion”,Teil 1), 105 et seq., Thieme Stuttgart 1980, and UK Patent Specification722,911. The catalyst is conveniently a “poisoned” one of the Lindlartype, preferably 5% palladium on calcium carbonate poisoned with 3.5%lead, and the temperature and pressure are suitably in the range fromabout 5° C. to about 50° C. and about 1 to about 5 bar (about 0.1 toabout 0.5 MPa), respectively. As the solvent there is suitably employedan organic solvent of relatively low polarity, e.g. an alkanol or analiphatic ester, preferably ethyl acetate. Moreover, the (poisoned)catalyst can be advantageously modified by addition of anitrogen-containing compound, such as quinoline.

Following the R²H elimination step, or in the aforementioned case theadditional hydrogenation step, the pertinent isolated and optionallypurified product, being retinal or the product of the formula I′ or I″,as appropriate, is normally present as an isomeric mixture, inparticular as a mixture of four isomers in respect of the 9- and13-double bonds, said isomeric mixture being designated conventionallyas the (9 E/Z, 13 E/Z) isomer.

In the case where a compound of the formula I′ (starting from the5-substituted 1,4-pentadiene or penta-1-en-4-yne derivative of theformula IIb or IIe, via the compound of the formula IVb or the compoundsof the formulae IVe and Vb, respectively) is produced, or alternativelywhere a compound of the formula I″ (starting from the 5-substituted1-pentene derivative of the formula IIc, via the compound of the formulaIVc) is produced, the respective product is then isomerized to thedesired retinal of the formula I. Conditions for the pertinentisomerization with a base, an acid or a metal catalyst are known per seand are described for example in J. Am. Chem. Soc. 108, 2090 et seq.(1986) and Chem. Ber. 118, 348 et seq. (1985) using1,8-diazabicyclo[5.4.0]undec-7-ene and alumina in ether, respectively,as the base; in EP 647,624 and J. Chem. Res. Synop. 296 et seq. (1987)in respect of acidic conditions; and in J. Chem. Soc. Perkin Trans. 1,1593 et seq. (1984) and Tetr. Lett. 1979, 1499 et seq. for theisomerization in the presence of the nonacarbonyl di-iron complex[Fe₂(CO)₉; in benzene] and the tri(triphenylphosphinyl)-rhodium chloridecomplex [Rh(PPh₃)₃Cl], respectively, as the metal catalyst.

If desired the so-produced retinal, predominantly in the (9 E/Z, 13E/Z)-isomeric form, can then be isomerized to the generally desiredisomeric form of retinal, (all-E)-retinal. The isomerization can beeffected under conventional isomerizing conditions, and a particularlypreferred method involves the acid-catalysed formation of an adduct of(principally) (all-E)-retinal with hydroquinone from the retinalproduced as defined and described above, and initially in theessentially (9 E/Z, 13 E/Z)-isomeric form, and the hydroquinone in anorganic solvent in which the adduct itself is sparingly soluble, therebyaffording the desired (all-E)-retinal-hydroquinone adduct in crystallineform. This adduct formation represents a further aspect of the presentinvention. As the acid catalyst there is suitably used hydrochloric acid(especially about 37%), hydrobromic acid (48%) or hydriodic acid (47%),p-toluenesulphonic acid or elemental iodine. The molar ratio of retinalstarting material: hydroquinone is suitably about 1:0.5, and the twocomponents are conventionally brought together in an organic solvent inwhich the adduct itself is sparingly soluble, such as a lower aliphatichydrocarbon, e.g. pentane or hexane; or a lower aliphatic ether, e.g.diethyl ether. The preferred solvent is diethyl ether or a mixture ofsaid ether and hexane. On leaving the two adduct components in such asolvent with a trace amount of the acid catalyst at ambient temperaturethe crystallization of the (all-E)-retinal-hydroquinone adduct generallyoccurs after a relatively short time, e.g. about one hour. Thecrystalline adduct can then be readily removed from the liquid medium byfiltration and if desired washed, e.g. with a solvent usable for theformation and as mentioned above, and dried, preferably at roomtemperature under reduced pressure. Such conventional methodology forthe formation and isolation of the (all-E)-retinal-hydroquinone isdescribed for example in U.S. Pat. No. 3,013,081 and French PatentPublications 1,288,975 and 1,291,622.

As an alternative to the prior isolation and optional purification ofthe retinal formed in the above defined/described two- or three-stepprocess (not the three- or four-step process starting from the5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1-en-4-yne derivative of theformula IId or IIe and involving the additional hydrogenation step) ofthe present invention in those cases where the R²H-elimination (secondprocess step) is acid-induced and the above-described acid-catalysedretinal-hydroquinone adduct formation is intended, said second processstep and the retinal-hydroquinone adduct formation step can be combined,thus avoiding the intermediate isolation and optional purification ofthe retinal prior to be adduct formation. In this alternative thesolvent used for the acid-induced R²H elimination reaction, if not onein which the adduct would readily dissolve, such as a halogenatedaliphatic hydrocarbon, must be replaced, on completion of theelimination reaction, by one in which the adduct is insoluble orsparingly soluble. Such a replacement solvent is suitably a loweraliphatic hydrocarbon, e.g. pentane or hexane, or a lower aliphaticether, e.g. diethyl ether, i.e. a solvent indicated above as beingsuitable for the “separate” adduct formation. The solvent replacement issuitably effected by evaporating off the “unsuitable” one under reducedpressure and adding the suitable one. Thereafter the hydroquinone isadded and the procedure for crystallization and isolation of theresulting crystalline (all-E)-retinal-hydroquinone adduct effected asdescribed above for the “separate” adduct formation.

The so-obtained (all-E)-retinal-hydroquinone adduct can be converted tothe further useful end product vitamin A alcohol (retinol) in thepredominantly (all-E)-isomeric form by methods known per se, for exampleby direct catalytic reduction with hydrogen using a ruthenium catalyst,as described in J. Molec. Catalysis 79, 117–131(1993), ibid. 66, L 27–L31 (1991) and U.S. Pat. No. 4,906,795. This reduction can also beeffected with sodium borohydride, as described in Chem. Lett. 1975, 1201et seq., which also indicates how retinol can be converted to vitamin Aacetate by acetylation with acetic anhydride in pyridine.

With the exception of the compounds of the formula IIa whereinsimultaneously R¹ signifies hydroxyl and R² signifies arylsulphonyl, thestarting 5-substituted pent(adi)en(yn)e derivatives of the formulae Ia,IIb, IIc, IId and IIe are novel compounds and constitute a still furtheraspect of the present invention.

Those novel starting materials of the formulae IIa, IIb and IIc can beproduced using the principles from the state of the art pertinent toadditions to terminal triple bonds, using as starting materialsappropriate acetylenic compounds of the formulae

(for ultimately producing the starting materials of the formulae IIa,IIb and IIc, respectively, featuring R¹ as hydroxyl), or, asappropriate, the corresponding acetylenic compounds in which the groupOR³ is present instead of the hydroxyl group. Accordingly, the lattercompounds have the following formulae VIa′, VIb′ and VIc′:

wherein R³ has the pertinent significance given above, i.e. signifiesC₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl, aroyl, (C₁₋₆-alkoxy)-carbonyl,tri(C₁₋₆-alkyl)silyl, di(C₁₋₆-alkyl)phosphonyl, diarylphosphonyl,(C₁₋₆-alkyl)sulphonyl or arylsulphonyl. The starting acetylenic compoundof the formula VIa, VIb, VIc, VIa′, VIb′ or VIc′ is reacted in each casewith a compound supplying the R² moiety, especially the compound of theformula R²H. The reaction conditions are in each case in general thoseemployed for organometallic reactions, i.e. the use of in particular anethereal solvent, e.g. a lower aliphatic ether, e.g. diethyl ether ordimethoxyethane, or a cyclic ether, e.g. tetrahydrofuran, and lowreaction temperatures, e.g. about −100° C. to about 0° C., particularlyabout −70° C. to about −40° C. (see Organometallics in Synthesis, AManual, Ed. M. Schlosser, p. 126, 1994 John Wiley & Sons Ltd.).

Examples of specific literature references providing the principles foreffecting the pertinent addition reactions of such a starting acetyleniccompound with a compound of the formula R²H, classified according to thenature of the group R², are as follows:

-   R² signifies C₁₋₆-alkoxy: EP 274,600; Tetr. Lett. 40, 6193–6195    (1999), Synlett 7, 880 et seq. (1996) and J. Org. Chem. USSR (Engl.)    6, 903 et seq. (1970);-   R² signifies C₁₋₆-alkylthio or arylthio: Tetr. Lett. 24, 61 et    seq. (1983) and Tetr. Lett. 25, 189 et seq. (1984);-   R² signifies (C₁₋₆-alkyl)carbonyloxy or aroyloxy: Bull. Soc. Chim.    Fr. 133, 939–944 (1996), Organomet. 15, 3998–4004 (1996) and J.    Organomet. Chem. 551, 151–157 (1998);-   R² signifies arylsulphonyl: Tetrahedron 46, 7197–7206 (1990);-   R² signifies chlorine or bromine: Org. Reactions 13, 150 et    seq. (1963) and Tetr. Lett. 32, 5861–5864 (1991);

Those novel starting 5-substituted pent(adi)ene derivatives of theformulae IIa, IIb and IIc wherein R¹ signifies hydroxyl and R² signifiesone of the previously given (selected) groups R² or signifies aryloxy,tri(C₁₋₆-alkyl)silyloxy, di(C₁₋₆-alkyl)phosphonyloxy,(C₁₋₆-alkyl)sulphonyloxy, arylsulphonyloxy, (C₁₋₆-alkyl)sulphonyl,di(C₁₋₆-alkyl)amino, N-aryl-(C₁₋₆-alkyl)amino or diarylamino can (also)be produced according to the two-step process represented schematicallyas follows:

In each case the reaction conditions are generally those employed forthe same type of reaction as described in the aforementionedOrganometallics in Synthesis article edited by M. Schlosser, as well asin J. Org. Chem. 23, 1063 et seq. (1958) and J. Org. Chem. 43, 1595 etseq. (1978).

Those 5-substituted pent(adi)ene derivatives of the formulae IIa, IIband IIc wherein R² signifies chlorine or bromine can also be produced by“indirect” addition of HCl or HBr, respectively, to the triple bond ofthe pertinent starting acetylenic compounds of the formulae VIa, VIb,VIc, VIa′, VIb′ and VIc′ by initial addition of an organic boroncompound [see, for example, J. Org. Chem. 54, 6068 et. seq. (1989),Tetr. Lett. 39, 3103–3106 (1998), Synth. Commun. 11, 247 et seq. (1981),Synth. Commun. 1983, 1027 et seq. and J. Chem. Soc. Perkin Trans. 1,2725–2726 (1992)], an alkyl aluminium hydride [Tetr. Lett. 29, 6243 etseq. (1988)], stannic hydride [Synth. 1986, 453 et seq., J. Am. Chem.Soc. 106, 5734 et seq. (1984), Tetr. Lett. 39, 6099 et seq. (1998) andHelv. Chim. Acta 66, 1018 et seq. (1983)] or a zirconium compound [J.Org. Chem. 56, 2590 et seq. (1991), Synth. 1993, 377–379, and Tetr.Lett. 31, 7257 et seq. (1990)], followed by the halogenation of therespective intermediate product with a halogenating agent such aselemental chlorine or N-chlorosuccinimide or, respectively, elementalbromine or N-bromosuccinimide.

An alternative method for producing those 5-substituted pent(adi)enederivatives of the formulae Ia, IIb and IIc wherein R¹ signifieshydroxyl and R² signifies C₁₋₆-alkoxy is also based upon the principlesdescribed in such literature as Organometallics in Synthesis, A Manual,Ed. M. Schlosser, p. 126, 1994 John Wiley & Sons Ltd., as well as in J.Org. Chem. 23, 1063 et seq.(1958) and J. Org. Chem. 43, 1595 et seq.(1978). According to the method β-ionone, α-ionone or retro-ionone, ofthe formula Xa, Xb or Xc, respectively,

is reacted with the appropriate cis-1-lithio-2-alkoxyethylene (cisLiCH═CHOC₁₋₆-alkyl) in an ethereal solvent at temperature of about −100°C. to about 0° C. As the ethereal solvent there is especially employed alower aliphatic ether, e.g. diethyl ether or dimethoxyethane, or acyclic ether, e.g. tetrahydrofuran. The reaction is preferably effectedat temperature of about −70° C. to about −40° C. Furthermore, thestarting cis-1-lithio-2-alkoxyethylene is conveniently prepared in situfrom the corresponding cis-1-bromo-2-alkoxyethylene (cisBrCH═CHOC₁₋₆-alkyl) and n-butyllithium or sec. butyllithium (aboutequimolar amounts of the two reactants) or tert. butyllithium (In aboutdouble the molar amount relative to the amount of ethylene derivativeemployed) using the same solvent and reaction temperature as given abovefor the ensuing reaction with the so-produced 1-lithio-2-alkoxyethylene.The ultimately produced 5-substituted pent(adi)ene derivative isconveniently isolated from the mixture after completed reaction byaddition of water thereto and extraction with a water-immiscible organicsolvent, particularly an aprotic such solvent, such as a lower aliphatichydrocarbon, e.g. hexane; an aromatic hydrocarbon, e.g. toluene; a lowerhalogenated aliphatic hydrocarbon, e.g. methylene chloride orchloroform; a lower aliphatic or cyclic ether, e.g. diethyl ether,tetrahydrofuran or dioxan; or a halogenated aromatic hydrocarbon, e.g.chlorobenzene. After removal of the extracting solvent, suitably atsomewhat elevated temperature and reduced pressure, the appropriatedesired 5-substituted 1-alkoxy-3-methyl-3-hydroxy-pent(adi)ene of theformula IIa, IIb or IIc is generally obtainable in good purity and inpractically quantitative yield. It does not normally have to be purifiedfurther before use in the process of the present invention involvingreaction with the 1,3-butadiene derivative of the formula III.

The precursors of the formulae VIa, VIb and VIc, as also the precursorsof the formulae Xa, Xb and Xc, are known compounds. Literaturereferences concerning these precursors include, for example, in respectof

-   precursor VIa: German Patent Publication (DE) 2,731,284;-   precursor VIb: Can. J. Chem. 46, 3041 et seq. (1968); and-   precursors VIc and Xc: PCT Patent Publication WO 00/002,854 A1 and    Bull. Soc. Chim. Fr. 132, 696 et seq. (1995).    The precursors of the formulae Xa and Xb are commercially available.

Only certain precursors of the formulae VIa′, VIb′ and VIc′ are knowncompounds, e.g. the compounds of the formula VIa′ wherein R³ is methylor ethyl (see DE 2,321,141 and U.S. Pat. No. 4,035,425); of the formulaVIb′ wherein R³ is acetyl (see WO 00/002,854 A1); of the formula VIa′wherein R³ is benzoyl [see J. Am. Chem. Soc. 102, 6355 et seq. (1980),ibid. 104, 6115 et seq. (1982), ibid. 107, 1028 et seq. (1985) and ibid.107, 1034 et seq. (1985)]; of the formula VIb′ wherein R³ ismethoxycarbonyl (see EP 647,624); and of the formula VIa′ wherein R³ istriethylsilyl [see J. Org. Chem. 63, 8704 et seq. (1998)].

The remaining precursors of the formulae VIa′, VIb′ and VIc′ can beproduced from the respective precursors of the formulae VIa, VIb and VIcby the following methods, according to the nature of the group R³:

-   R³ signifies C₁₋₆-alkyl: as described in DE 2,321,141 and U.S. Pat.    No. 4,035,425 (R³ is methyl or ethyl: see above) or analogously to    the pertinent method;-   R³ signifies (C₁₋₆-alkyl)carbonyl: as described in WO 00/002,854 A1    or J. Org. Chem. 56, 5349 et seq. (1991) or analogously to the    pertinent method by alkanoylation of the respective compound of the    formula VIa, VIb or VIc with the appropriate carboxylic acid    anhydride, e.g. acetic anhydride, in the presence of a base;-   R³ signifies aroyl: as described in J. Am. Chem. Soc. 102, 6355 et    seq. (1980), ibid. 104, 6115 et seq.(1982), ibid. 107, 1028 et    seq.(1985) or ibid. 107, 1034 et seq. (1985), or analogously to the    pertinent method by aroylation of the respective compound of the    formula VIa, VIb or VIc with the appropriate aromatic acid anhydride    in the presence of a base;-   R³ signifies (C₁₋₆-alkoxy)carbonyl: as described in EP 647,624 or    analogously to the pertinent method by reaction of the respective    compound of the formula VIa, VIb or VIc with the appropriate    alkoxycarbonyl chloride in the presence of a base;-   R³ signifies tri(C₁₋₆-alkyl)silyl: as described in J. Org. Chem. 63,    8704 et seq. (1998) or analogously to the pertinent method by    reaction of the respective compound of the formula VIa, VIb or VIc    with the appropriate trialkylsilyl chloride in the presence of a    base, e.g. triethylamine or dimethylaminopyridine;-   R³ signifies di(C₁₋₆-alkyl)phosphonyl or diarylphosphonyl:    analogously to the pertinent method described in J. Org. Chem. 54,    627 et seq. (1989) by reaction of the respective compound of the    formula VIa, VIb or VIc with an appropriate dialkyl chlorophosphite    and subsequent oxidation of the so produced phosphite to the    phosphate, or analogously to the pertinent method described in Tetr.    Lett. 1984, 4195 et seq. by reaction of the respective compound of    the formula VIa, VIb or VIc with an appropriate dialkyl or diaryl    chlorophosphate in the presence of a base.-   R³ signifies (C₁₋₆-alkyl)sulphonyl or arylsulphonyl: analogously to    the pertinent method described in Synlett 1053 et seq. (1999) or    Tetrahedron 55, 6387 et seq. (1999) by reaction of the respective    compound of the formula VIa, VIb or VIc with an appropriate    alkanesulphonic acid chloride or arylsulphonic acid chloride in the    presence of a base, e.g. triethylamine or pyridine.

The precursors of the formulae VIIa, VIIb and VIIc can be produced fromβ-ionone, α-ionone and retro-ionone (compounds of the formulae Xa, Xband Xc respectively, given above) by a haloform degradation reaction, inparticular with bromine in aqueous sodium hydroxide according to themethod described on pages 325–326 in Carotenoids Volume 2: Synthesis,Ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhäuser Verlag BaselBoston Berlin 1996, to afford the appropriate β-substituted acrylic acidof the formula XIa or XIb or γ-substituted vinylacetic acid of theformula XIc,

respectively, followed by a Hunsdiecker reaction, e.g. withN-bromosuccinimide, according to the method described in Tetrahedron 43,4601–4608 (1987), to produce the compound of the formula VIIa, VIIb orVIIc, respectively.

The precursors of the formula IX are in some cases known compounds andotherwise can be produced analogously to the known ones; the pertinentliterature for the various types of the group R² is given hereafter:

-   R² signifies chlorine or bromine: J. Chem. Soc. Perkin Trans. 1990,    3317–3319;-   R² signifies C₁₋₆-alkoxy: Collect. Czech. Chem. Commun. 1992,    1072–1080, which describes the production of the precursor of the    formula IX wherein R² signifies ethoxy; the corresponding compound    with R² as methoxy is commercially available.-   R² signifies C₁₋₆-alkylthio or arylthio: J. Org. Chem. 46, 235 et    seq. (1981);-   R² signifies aryloxy: Fette, Seifen, Anstrichmittel 82, 82–86    (1980);-   R² signifies (C₁₋₆-alkyl)carbonyloxy or aroyloxy: J. Org. Chem. 50,    1955–1959 (1985);-   R² signifies tri(C₁₋₆-alkyl)silyloxy: Liebigs Ann. Chem. 12, 2352 et    seq. (1985);-   R² signifies di(C₁₋₆-alkyl)phosphonyloxy: Swiss Patent No. 490,016;-   R² signifies (C₁₋₆-alkyl)sulphonyl or arylsulphonyl: Aust. J. Chem.    41, 881 et seq. (1988);-   R² signifies di(C₁₋₆-alkyl)amino, N-aryl-(C₁₋₆-alkyl)amino or    diarylamino: Org. Prep. Proced. Int. 16, 31–36 (1984).

In the case of the precursor of the formula IX wherein R² signifies(C₁₋₆-alkyl)sulphonyloxy or arylsulphonyloxy the compounds are novel,and no analogous methods for their production are known. However, theycan be produced by reaction of 3-keto-butyraldehyde with the respectivealkane- or arylsulphonyl chloride in a solvent such as tetrahydrofuranand in the presence of a base, e.g. triethylamine. J. Heterocyclic Chem.1991, 885–890, and J. Chem. Soc. Perkin Trans. 1, 1992, 2855–2861,respectively, provide pertinent information as to the methodology.

The alternative novel starting materials for the process of the presentinvention, i.e. the 5-substituted penta-1-en-4-yne derivatives of theformulae IId and IIe, can be produced from the known1-ethynyl-2,6,6-trimethyl-cyclohex-1-ene or -2-ene, respectively, of theformula

[(see U.S. Pat. No. 2,775,626 and Tetrahedron 55, 15071–15098 (1999),and Swiss Patent Specification 651,287, respectively, for the productionof each 1-ethynyl-2,6,6-trimethyl-cyclohexene itself] by condensationreaction under deprotonating strongly basic and anhydrous conditionswith a ketone of the formula IX, given above, in an inert organicsolvent. As the strong base there is suitably used a base which iscustomary for the deprotonation of acetylenes, especially a lithium-,sodium- or magnesium-containing base. Examples of such bases arelithium-organic compounds such as methyllithium, butyllithium orphenyllithium, Grignard reagents such as alkylmagnesium halides anddialkylmagnesium, amides such as lithium amide and sodium amide, andhydrides such as lithium hydride and sodium hydride, the preferred basebeing an alkyllithium or an alkylmagnesium chloride. As the solventthere is suitably used an aliphatic or cyclic ether, e.g. diethyl etheror, respectively, tetrahydrofuran or dioxan; or an aliphatic or aromatichydrocarbon, e.g. hexane or a petroleum ether or, respectively, benzene,toluene or an xylene. The preferred solvent for the reaction istetrahydrofuran. The ketone of formula IX is preferably used in anequivalent amount or slight excess, e.g. 1.1 to 1.3 equivalents perequivalent of the 1-ethynyl-2,6,6-trimethyl-cyclohexene of the formulaXIIa or XIIb. However, a larger excess is not necessarily detrimental tothe outcome of the condensation reaction. Furthermore, a slight excessof base relative to the amount of the compound of the formula XIIa orXIIb, for example about 1.1 to 1.3 equivalents, is suitably used.Moreover, it is possible to effect the condensation reaction in theadditional presence of an inorganic lithium or cerium salt, which isknown to slightly increase the yield of the reaction. Examples of suchsalts are lithium halides, cerium halides and lithium tetrafluoroborate,cerium trichloride and lithium bromide being the preferred salts. Theamount of lithium or cerium salt is not critical and can amount to, forexample, about 0.5 to about 2.0 equivalents per equivalent of the amountof the compound of the formula XIIa or XIIb. Regardless of theparticular above-indicated conditions employed the condensation issuitably effected at temperatures from about −80° C. to about 10° C.,preferably from about −70° C. to about −50° C. The condensation reactionaffords those 5-substituted penta-1-en-4-yne derivatives of the formulaeIId and IIe wherein R¹ signifies hydroxyl. The remaining 5-substitutedpenta-1-en-4-yne derivatives of the formulae lid and IIe, i.e. thosewherein R¹ signifies a group OR³, can be produced from the formerderivatives by analogous methods for producing the precursors of theformulae VIa′, VIb′ and VIc′ from the respective precursors of theformulae VIa, VIb and VIc, as indicated hereinabove by mention ofpertinent references for the hydroxyl->OR³ group transformation.

This condensation reaction affords, as indicated above, the starting5-substituted penta-1-en-4-yne derivative of the formula IId or IIe fordirect use in the process of the present invention, i.e. for reactingwith the 1,3-butadiene derivative of the formula III. However, insteadof such direct use, the derivative can be converted to the otheremployable starting material, viz. the 5-substituted 1,4-pentadienederivative of the formula Ia or IIb, respectively, by selectivereduction with a complex metal hydride, preferably a hydrido-aluminate,most preferably sodium bis(2-methoxcyethoxy)aluminium hydride, underconditions described in the literature, e.g. analogous to the proceduresdescribed in Helv. Chim. Acta 73, 868–873 (1990) and U.S. Pat. Nos.4,952,716 and 5,227,507. The reduction is conveniently carried out in aninert organic solvent, examples of such being those solvents given abovein connection with the reaction of the1-ethynyl-2,6,6-trimethyl-cyclohexene of the formula XIIa or XIIb withthe ketone of the formula IX, especially the solvents referred to thereas being preferred. The temperature and pressure by which the selectivereduction is carried out are not critical. As the reduction proceedsrapidly, the reduction is preferably carried out at temperatures fromabout −50° C. to about 30° C., more preferably at temperatures fromabout −10° C. to about 0° C., and at atmospheric pressure. The reducingagent can be used in an about equivalent amount, or preferably in excessamount, relative to the amount of starting 5-substitutedpenta-1-en-4-yne derivative of the formula IId or IIe. An amount whichis at least about 1.1 equivalents, for example 1.2 to 1.4 equivalents,per equivalent of said derivative is preferred. However, a larger excessis not necessarily detrimental to the outcome of the selectivereduction.

The hydrolysis of the aluminium-complex, formed as the intermediate inthe above-described selective reduction, to the desired 5-substituted1,4-pentadiene derivative of the formula IIa or IIb can be effected in amanner known per se, for example, by treatment with water in thepresence of an organic or inorganic acid such as p-toluenesulphonicacid, or more preferably in the presence of an alkali, such as in sodiumhydroxide solution. The temperature and pressure are not critical.However, in general) the hydrolysis is carried out at atmosphericpressure and room temperature or a lower temperature, preferably attemperatures from about 0° C. to room temperature.

The 1,3-butadiene derivatives of the formula III used as startingmaterials in the first step of the process of the present invention areeither known compounds or can be produced analogously to the knowncompounds, for example according to the methods described in Bull. Soc.Chim. Fr. 130 (2), 200–205 (1993), Tetr. Lett. 22 (29), 2833–2836 (1989)and ibid. 26 (47), 8591–8594 (1995).

The invention is illustrated by the following Examples:

EXAMPLE 1 Preparation of (1Z,4E)-1-ethoxy-3-methyl-3-hydroxy-5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadiene

To 750 ml of tetrahydrofuran in a 750 ml reaction flask equipped with amagnetic stirrer and argon gasification means were added under the argonatmosphere 17.6 ml (approx. 25 g, 0.16 mol) ofcis-1-bromo-2-ethoxyethylene, and the mixture was then cooled to −70° C.210 ml (0.32 mol) of tert. butyllithium (1.5 molar solution in hexane)were then slowly added to the stirred mixture under maintenance of atemperature of −70° C. to −60° C., the addition being completed withinabout 30 minutes. After stirring the mixture for a further 30 minutes at−70° C. a solution of 20.2 g (0.103 mol) of β-ionone (approx. 98% pure)in 60 ml of tetrahydrofutran was slowly added, maintaining thetemperature of the mixture at −70° C. to −60° C. The reaction mixturewas then stirred at −70° C. for 3 hours, after which the reaction wasestablished by HPLC to have been completed.

The cooling means was removed and 200 ml of ice/water were added to theflask contents within about 10 minutes. After the mixture had reached atemperature of 0° C. it was poured into 250 ml of hexane, and the wholewas washed successively with three 200 ml quantities of water and two200 ml quantities of saturated sodium chloride solution. Then thecombined aqueous phases were extracted with 250 ml of hexane. Thecombined hexane phases were dried over anhydrous sodium sulphate andafter removal of the drying agent by filtration concentrated at 35° C.under a reduced pressure of 100–200 mbar (10–20 kPa), followed by aconcentration at room temperature under high vacuum to remove the finaltraces of solvent. There resulted 30.25 g (quantitative yield) of (1Z,4E)-1-ethoxy-3-methyl-3-hydroxy-5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadieneas a pale yellow oil.

¹H-NMR (400 MHz, CDCl₃): 6.05 (d, J=16 Hz, 1 H). 5.99 (d=8 Hz, 1 H),5.54 (d, J=16 Hz, 1 H), 4.60 (d, J=8 Hz, 1 H), 3.84 (q, J˜8 Hz, 2 H),1.95 (t, J˜8 Hz, 2 H), 1,65 (s, 3 H), 1.6 (m, 2 H), 1.45 (m, 2 H), 1.25(t, J˜8 Hz, 3 H), 0.98 (1s, 3 H); IR (Film, cm⁻¹): 1659 (C=0), 1102(C—O—C); MS: 264.3 (M⁺).

EXAMPLE 2 Preparation of (1Z,4E)-1-ethoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-2-enyl)-penta-1,4-dien-3-ol

Using an analogous procedure to that described in Example 1 14.32 g (92%yield) of the titled product were obtained from 10.10 g (50 mmol) ofα-ionone.

¹H-NMR (400 MHz) CDCl₃): 5.96 (m, 1 H), 5.59 (d, J=12 Hz, 1 H). 5.45(d=11 Hz, 1 H), 5.39 (m, 1 H), 4.57 (d, J=8 Hz, 1 H), 3.82 (q, J˜8 Hz, 2H), 2.13 (d, J˜9 Hz, 1 H), 1,98 (s, 2 H), 1.53 (m, 2H), 1.36 (m, 3 H),1.27 (t, J˜8 Hz, 3 H), 0.93 (s, 3 H), 0.84 (s, 3 H); IR (Film, cm⁻¹):1658 (C═C), 1103 (C—O—C); MS: 264.3 (M⁺).

EXAMPLE 3 Preparation of 2-(5-ethoxy-3-methoxy-3-methyl-(1E,4Z)-penta-1,4-dienyl)-1,3,3-trimethyl-cyclohexene

0.8 ml (approx. 5.6 mmol) of potassium hydride (35% suspension in) underargon atmosphere in a 25 ml Schlenk tube equipped with a stirring barwere washed three times with hexane and decanted. After the addition of0.72 ml (7.5 mmol) of dimethyl sulphate at ambient temperature 1.43 g (5mmol) of (1Z,4E)-1-ethoxy-3-methyl-5-(2,6,6-tri-methyl-cyclohex-1-enyl)-penta-1,4-dien-3-oldissolved in 3 ml of dry tetrahydrofuran was added dropwise.

After the mixture had been stirred for 18 hours at ambient temperature,the reaction was quenched with 1.5 ml of 25%-ammonia and stirred for afurther 30 minutes. The solution was then diluted with 50 ml of hexaneand extracted with three 25 ml quantities of water and two 25 mlquantities of brine. The aqueous phases were re-extracted with 50 ml ofhexane. The combined organic phases were concentrated under reducedpressure to yield 1.498 g (98% yield) of2-(5-ethoxy-3-methoxy-3-methyl-(1E,4Z)-penta-1,4-dienyl)-1,3,3-trimethyl-cyclohexene as a yellowish oil.This was sufficiently pure for further reaction.

¹H-NMR (400 MHz, CDCl₃): 6.05 (d, J=16 Hz, 1 H). 5.99 (d, J=8 Hz, 1 H),5.48 (d, J=16 Hz, 1 H), 4.61 (d, J=7 Hz, 1 H), 3.81 (q, J=7 Hz, 2 H),3.23 (s, 3 H), 1.97 (t, J˜7 Hz, 2 H), 1,68 (s, 3 H), 1.6 (m, 2 H), 1.51(s, 3 H), 1.45 (m, 2 H), 1.23 (t, J˜8 Hz, 3 H), 0.98 (s, 6 H); IR (Film,cm⁻¹): 1660 (C═C), 1105 (C—O—C); MS: 278.2 (M⁺).

EXAMPLE 4 Preparation of3-methoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dienyl benzoate

3.60 g (15 mmol) of2-(3-methoxy-3-methyl-(E)-pent-1-en-4-ynyl)-1,3,3-trimethyl-cyclohexene,2.76 g of benzoic acid) 20 ml of toluene and 90 mg (0.15 mmol) ofbis-(2-methylallyl)-ethylene-bis-diphenyl-phosphine-ruthenium(II)-complexwere introduced into a two-necked flask equipped with a stirring bar, arubber septum and an argon inlet under an argon atmosphere. Afterstirring for 12 hours at ambient temperature the reaction mixture washeated to 45° C. for 4 hours for the completion of the reaction.

Subsequently all the volatile material was removed under a reducedpressure of 100–150 mbar (10–15 kPa) and the resulting brown oil waspurified by column chromatography using 50 g of silica gel (0.04–0.063mm) as the stationary phase and a 9:1 (v/v) mixture of hexane and ethylacetate as the eluting agent. In this way there were obtained 2.67 g(approx. 50% yield) of3-methoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dienyl benzoate.

¹H-NMR (400 MHz, CDCl₃): 8.09 (d, J=7 Hz, 2 H), 7.60 (t, J=7 Hz, 1 H),7.46 (t, J=8 Hz, 2 H), 7.38 (d, J=7 Hz, 1 H). 6.14 (d, J=16 Hz, 1 H),5.57 (d, J=16 Hz, 1 H), 5.11 (d, J=7 Hz, 1 H), 3.28 (s, 3 H), 1.96 (t,J˜6 Hz, 2 H), 1,65 (s, 3 H), 1.63 (s, 3 H), 1.57 (m, 2 H), 1.43 (m, 2H), 0.97 (s, 3 H), 0.96 (s, 3 H); IR (Film, cm⁻¹): 1737 (C═O), 1667(C═C), 1095 (C—O—C); MS: 354.2 (M⁺).

EXAMPLE 5 Preparation of3-hydroxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z.4E)-penta-1,4-dienyl benzoate

Using an analogous procedure to that described in Example 4, 9.75 g (95%yield) of 3-hydroxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dienyl benzoate were obtained from 6.60 g (30 mmol) of(E)-3-methyl-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-4-yn-3-ol asa crude product which was sufficiently pure for further reaction.

¹H-NMR (400 MHz, CDCl₃): 8.07 (d, J=7 Hz, 2 H), 7.61 (t, J=7 Hz, 1 H),7.47 (t, J=8 Hz, 2 H), 7.31 (d, J=7 Hz, 1 H). 6.19 (d, J=16 Hz, 1 H),5.53 (d, J=16 Hz, 1 H), 5.22 (d, J=7 Hz, 1 H), 1.96 (t, J˜6 Hz, 2 H),1,65 (s, 6 H), 1.59 (m, 2 H), 1.45 (m, 2 H), 0.98 (s, 6 H); IR (Film,cm⁻¹): 1738 (C═O), 1666 (C═C); MS: 340.2 (M⁺).

EXAMPLE 6 Preparation of1-ethoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-2-enylidene)-(Z)-pent-1-en-3-ol

Using an analogous procedure to that described in Example 1, 2.64 g (43%yield) of the titled product were obtained from 4.67 g (23.1 mmol) ofretro-ionone after chromatographic purification using 30 g of silica gel(0.04–0.063 mm) as the stationary phase and a 98:2 (v/v) mixture ofhexane and ethyl acetate as the eluting agent.

¹H-NMR (400 MHz, CDCl₃): 5.96 (d, J=7 Hz, 1H). 5.61 (br s, 1 H), 5.56(t, J=7 Hz, 1 H), 4.51 (d, J=7 Hz, 1 H), 3.84 (q, J=8 Hz, 2 H), 2.70(dd, J=18 Hz, J=7 Hz, 1 H), 2.59 (dd, J=18 Hz, J=7 Hz, 1 H), 2.06 (br s,2 H), 1,83 (s, 3 H), 1.45 (m, 2 H), 1.36 (s, 3H), 1.28 (t, J˜8 Hz, 2 H),1.19 (s, 6 H); IR (Film, cm⁻¹): 1659 (C═C), 1100 (C—O—C); MS: 247.2(M⁺-OH).

EXAMPLE 7 Preparation of 2-(5-ethoxy-3-methyl-3-trimethylsilyloxy-(1E,4Z)-penta-1,4-dienyl)-1,3,3-trimethyl-cyclohexene

In a 100 ml Schlenk tube equipped with a stirring bar and a rubberseptum 2.95 g (10 mmol) of1-ethoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dien-3-ol were dissolved in a mixture of 50 ml of drydimethylformamide, 0.50 g (0.4 mmol) of 4-dimethylamino-pyridine and 7.0ml (50 mmol) of triethylamine. The mixture was cooled to 0° C. and 5.0ml (40 mmol) of trimethylchlorosilane was introduced dropwise.

After the mixture had been stirred for 14 hours at ambient temperature,it was diluted with 250 ml of hexane and extracted with three 250 mlquantities of water, two 250 ml quantities of saturated sodiumbicarbonate solution and two 250 ml quantities of brine. The combinedorganic phases were dried over sodium sulphate and concentrated underreduced pressure to afford 3.49 g (93% yield) of2-(5-ethoxy-3-methyl-3-trimethylsilyloxy-(1E,4Z)-penta-1,4-dienyl)-1,3,3-trimethyl-cyclohexene as a yellowish oil.This was sufficiently pure for further reaction.

¹H-NMR (400 MHz, CDCl₃): 6.02 (d, J=16 Hz, 1 H). 5.81 (d, J=7 Hz, 1 H),5.64 (d, J=16 Hz, 1 H), 4.45 (d, J=7 Hz, 1 H), 3.75 (q, J=7 Hz, 2 H),1.97 (t, J˜6 Hz, 2 H), 1,66 (s, 3 H), 1.6 (m, 2 H), 1.55 (s, 3 H), 1.40(m, 2 H), 1.23 (t, J˜7 Hz, 3 H), 0.99 (s, 6 H), 0.14 (s, 9 H); IR (Film,cm⁻¹): 1660 (C═C), 1105 (C—O—C); MS: 336.3 (M⁺).

EXAMPLE 8 Preparation oftrans-1-chloro-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-4-yn-3-ol

A solution of 1.48 g (10 mmol) of 2-ethynyl-1,3,3-trimethyl-cyclohexenein 90 ml of dry tetrahydrofuran in a 250 ml three-necked reaction flaskequipped with a magnetic stirrer, a rubber septum and argon gasificationmeans was cooled under an argon atmosphere in a dry ice bath. It wastreated dropwise with 7.5 ml (12 mmol) of a 1.6 M solution ofn-butyllithium in hexane as fast as the temperature could be maintainedat −70 to −60° C. The addition was completed within 10 minutes. Afterthe reaction mixture had been stirred for an additional 30 minutes at−70° C., a solution of 1.045 g (10 mmol) of 4-chloro-buten-2-one in 10ml of dry tetrahydrofuran was added slowly. After further stirring for 3hours at −70° C. the reaction mixture was poured into 250 ml of icewater and extracted with three 70 ml quantities of hexane. The combinedorganic phases were washed with three 100 ml quantities of water and 50ml of brine, and dried over anhydrous magnesium sulphate. All thevolatile material was removed under a reduced pressure of 100–200 mbar(10–20 kPa), and 2.57 g of crude product were obtained. Chromatographythrough 60 of silica gel (0.04–0.063 mm) with a 95:5 (v/v) mixture ofhexane and ethyl acetate afforded 1.19 g (4.7 mmol, 47% yield) of thepure product.

¹H-NMR (400 MHz, CDCl₃): 6.56 (d, J=13 Hz, 1 H), 6.11 (d=13 Hz, 1 H),2.02 (t, J=6 Hz, 2 H), 1.86 (s, 3 H), 1.63 (s, 3 H), 1.60 (m, 2 H), 1.46(m, 2 H), 1.09 (s, 6 H) IR (Film, cm⁻¹): 3373 (OH), 2210 (C≡C); MS:252.2, 254.2 (M⁺).

EXAMPLE 9 Preparation of (1E,4E)-1-chloro-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1.4-dien-3-ol

1.96 g (7.5 mmol) of1-chloro-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-4-yn-3-olwere dissolved in 100 ml of dry tetrahydrofuran in a 250 ml Schlenk tubeequipped with a stirring bar and a rubber septum under an argonatmosphere and cooled to −10° C. 2.71 ml (9.5 mmol) ofsodium-dihydrido-bis-(2-methoxyethoxy)aluminate (3.5 M in toluene) wereadded dropwise using a syringe. After 4 hours stirring at −10° C. thereaction mixture was quenched by adding 5 ml of a 40% solution ofethanol in hexane at 0–5° C.

For the working-up the solution was treated with 13 ml of 28% aqueoussodium hydroxide solution at 0–5° C. for 10 minutes. The resultingemulsion was diluted with 110 ml of water and extracted twice with 50 mlof hexane. The combined organic phases were extracted with five 50 mlquantities of water and 50 ml of brine, and dried over magnesiumsulphate. After removal of all the volatile material at reduced pressureof 100–200 mbar (10–20 kPa) 1.94 g of crude product were obtained, whichcontained 94% of (1E,4E)-1-chloro-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1,4-dien-3-oland was sufficiently pure for further reaction.

¹H-NMR (400 MHz, CDCl₃): 6.28 (d, J=13 Hz, 1 H), 6.11 (d, J=16 Hz, 1 H),6.09 (d=13 Hz, 1 H), 5.51 (d, J=16 Hz, 1 H), 1.97 (t, J˜7 Hz, 2 H), 1.65(s, 3 H), 1.60 (m, 2 H), 1.45 (m, 2 H), 1.44 (s, 3 H), 0.98 (s, 6 H);MS: 254.2, 256.2 (M⁺).

EXAMPLE 10 Preparation of (9E/Z, 13 E/Z)-11,12-dihydro-11-ethoxy-retinal

12.3 g (approx. 42 mmol) ofcis-1-ethoxy-3-methyl-3-hydroxy-5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadiene(approx. 90% pure), 12.5 g (80 mmol) of1-trimethyl-silyloxy-3-methyl-1,3-butadiene and 60 ml of acetonitrilewere introduced into a 100 ml two-necked reaction flask equipped with amagnetic stirrer and argon gasification means. The mixture was cooled to−30° C. and 550 mg (approx. 4 mmol) of anhydrous zinc chloride wereadded with stirring under the argon atmosphere. The reaction mixture wasstirred successively for 1 hour at −30° C., 1 hour at 0° C. and 1 hourat room temperature, after which it was established by HPLC that thereaction had been completed to about 90%.

For the working-up 10 ml of a 9:1 mixture of glacial acetic acid andwater were added to the stirred mixture at room temperature, and themixture was stirred at this temperature for a further 30 minutes. Theresulting solution was added to 100 ml of water and the aqueous solutionextracted with two 200 ml quantities of hexane and the combinedseparated organic phases washed successively with three 100 mlquantities of water and three 100 ml quantities of saturated sodiumchloride solution. The separated hexane phase was dried over anhydroussodium sulphate and, after removal of the drying agent by filtration,concentrated at 35° C. under a reduced pressure of 100–200 mbar (10–20kPa). There resulted 15.6 g of crude product as an oil, which was thenpurified by column chromatography using 400 g of silica gel (0.04–0.063mm) as the stationary phase and a 9:1 (v/v) mixture of hexane and ethylacetate as the eluting agent. In this way there were obtained 8.84 g(approx. 64% yield) of pure (9 E/Z, 13E/Z)-11,12-dihydro-11-ethoxy-retinal as a yellow oil.

HPLC: Constitution of retinal isomers: 4.8% (9,13-di-cis), 7.4%(13-cis), 28.0% (9-cis) and 56.7% (all-E)[total 96.9 area percent (%)];¹H-NMR (400 MHz, CDCl₃): inter alia 4 doublets (CHO) at approx. 9.85–10(J˜8 Hz); MS: 247.2 (M⁺); IR (Film, cm⁻¹): 1676 (CH=0), 1633 (C═C), 1082(C—O—C); UV (Cyclohexane): 232 nm (Σ=49,100, log Σ=4.69).

EXAMPLE 11 Preparation of (2 E/Z 8E/Z)-5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enyl)-nona-2,6,8-trienal

Using an analogous procedure to that described in Example 10, 1.495 g(4.5 mmol, 59% yield) of (2 E/Z, 6 E, 8E/Z)-5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enyl)-nona-2,6,8-trienalwere obtained from 2.145 g (7.7 mmol) of (1Z,4E)-1-ethoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-2-enyl)-penta-1,4-dien-3-ol.

HPLC: Constitution of retinal isomers: 4.7% (9,13-di-cis), 7.9%(13-cis), 23.9% (9-cis) and 61.7% (all-E) [total 95.2 area percent (%)];¹H-NMR (400 MHz, CDCl₃): inter alia 4 doublets (CHO) at approx. 9.85–10(J˜8 Hz); MS: 330.2 (M⁺); IR (Film, cm⁻¹): 1676 (CH═O), 1633 (C═C), 1082(C—O—C);

EXAMPLE 12 Preparation of (9E/Z, 13E/Z)-11,12-dihydro-11-benzoyloxy-retinal

Using an analogous procedure to that described in Example 10, 970 mg(2.4 mmol, 48% yield) of (9E/Z, 13E/Z)-11,12-dihydro-11,12-benzoyloxy-retinal were obtained from 1.87 g(5.0 mmol) of3-methoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dienyl benzoate.

HPLC: Constitution of retinal isomers: 4.3% (9,13-di-cis), 8.5%(13-cis), 34.2% (9-cis) and 46.8% (all-E) ¹H-NMR (400 MHz, CDCl₃): interalia 4 doublets (CHO) at approx. 9.85–10 (J˜8 Hz); MS: 406.3 (M⁺); IR(Film, cm⁻¹): 1718(CO═O), 1677 (CH═O).

(9E/Z, 13 E/Z)-11,12-dihydro-11-benzoyloxy-retinal (266 mg, 52% yield)was also obtained from 935 mg (2.5 mmol) of3-hydroxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-(1Z,4E)-penta-1,4-dienyl benzoate and 380 mg (3.75 mmol) of1-methoxy-3-methyl-1,3-butadiene under analogous conditions.

HPLC: Constitution of retinal isomers: 3.9% (9,13-di-cis), 2.2%(13-cis), 28.0% (9-cis)and 54.4% (all-E).

EXAMPLE 13 Preparation of5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enylidene)-(2E/Z, 6E/Z)-nona-2,6-dienal

Using an analogous procedure to that described in Example 10, 1.404 g(4.3 mmol, 47.2% yield) of5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enylidene)-(2E/Z, 6E/Z)-nona-2,6-dienal were obtained from 2.380 g (9.0 mmol) of1-ethoxy-3-methyl-5-(2,6,6-trimethyl-cyclohex-2-enylidene)-(Z)-pent-1-en-3-ol.

HPLC: Constitution of isomers: 5.1%, 9.8%, 23.2% and 52.7% (all-E)(total95.1 area percent (%)]; ¹H-NMR (400 MHz, CDCl₃): inter alia 4 doublets(CHO) at approx. 9.85–10 (J˜8 Hz); MS: 330.5 (M⁺); IR (Film, cm⁻¹): 1675(CH═O), 1633 (C═C), 1083 (C—O—C).

EXAMPLE 14 Preparation of (9E,13E)-5-chloro-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-1-enyl)-nona-2,6-dien-8-ynal

Using an analogous procedure to that described in Example 10, 325 mg(1.0 mmol, 78% yield) of (9E,13E)-5-chloro-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-1-enyl)-nona-2,6-dien-8-ynalwere obtained from 330 mg (1.3 mmol) of1-chloro-3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-4-yn-3-ol.

¹H-NMR (400 MHz, CDCl₃): 9.99 (d, J=8 Hz, 1 H), 6.39 (d, J=13 Hz, 1 H),5.93 (d=8 Hz, 1 H), 5.87 (d, J=13 Hz, 1 H), 2.49 (d, J=13 Hz, 1 H), 2.41(d, J=13 Hz, 1 H), 2.26 (s, 3 H), 2.00 (t, J˜6 Hz, 2 H), 1.82 (s, 3 H),1.59 (m, 2 H), 1.45 (m, 2 H), 1.43 (s, 3 H), 1.06 (s, 6 H); IR (Film,cm⁻¹): 2211 (C≡C), 1676 (C═O); MS: 318.2, 320.2 (M⁺).

EXAMPLE 15 Preparation (9E/Z, 13 E/Z)-11,12-dihydro-11-chloro-retinal

Using an analogous procedure to that described in Example 303 mg (0.9mmol, 24.4% yield) of (9E/Z, 13 E/Z)-11,12-dihydro-11-chloro-retinalwere obtained from 1.21 g (3.9 mmol) of (1E,4E)-1-chloro-3-methyl-5-(2,6,6-trimethylcyclohex-1-enyl)-penta-1,4-dien-3-ol.

¹H-NMR (400 MHz, CDCl₃): inter alia 4 doublets (CHO) at approx. 9.85–10(J˜8 Hz); MS: 320.2 (M⁺).

EXAMPLE 16 Preparation of (9 E/Z, 13 E/Z)-retinal

To 2.48 g (7.5 mmol) of 11,12-dihydro-11-ethoxy-retinal in 22 ml oftoluene in a 25 ml two-necked reaction flask equipped with a magneticstirrer and argon gasification means were added 2.40 g (approx. 15 mmol)of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the reaction mixture wasstirred for 3 hours at 70° C. (according to HPLC and thin layerchromatographic analysis the elimination of ethanol had been completedat that stage). The resulting solution was then poured into 50 ml of 10%aqueous sulphuric acid and the whole extracted with two 100 mlquantities of hexane, and the combined organic phases were washedsuccessively with 50 ml of 10% aqueous sulphuric acid, three 100 mlquantities of water, two 50 ml quantities of saturated sodiumbicarbonate solution and finally two 50 ml quantities of sodium chloridesolution. After drying of the separated organic phase over anhydroussodium sulphate, and concentration at 35° C. under a reduced pressure of100–200 mbar (10–20 kPa) there were obtained 2.42 g of crude retinal asa E/Z-isomeric mixture. Chromatography though 60 g of silica gel(0.04–0.063 mm) with a 9:1 (v/v) mixture of hexane and ethyl acetateafforded 1.81 g (85% yield) of pure retinal (E/Z-isomeric mixture) as aviscous red oil.

HPLC: Constitution of retinal isomers: 6.8% (9,13-di-cis), 19.5%(13-cis), 20.1% (9-cis) and 52.7% (all-E) (total 99.1%); ¹H-NMR (400MHz, CDCl₃) inter alia 4 doublets (CHO) at 10.1–10.2 (J˜8 Hz); IR (Film,cm⁻¹): 1661 (CH═O), 1580 (C═C conjugated); MS: 284.2 (M⁺); UV(Cyclohexane): 367 (Σ=69,400, log Σ=4.84).

EXAMPLE 17 Preparation of (9 E/Z, 13 E/Z)-retinal from5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enylidene)-(2E/Z, 6E/Z)-nona-2,6-dienal

To a solution of 350 mg (1.0 mmol) of5-ethoxy-3,7-dimethyl-9-(2,6,6-trimethyl-cyclohex-2-enylidene)-(2E/Z, 6E/Z)-nona-2,6-dienal in 6 ml of acetone under argon atmosphere in a 10ml Schlenk tube, 0.05 ml of 48% hydrobromic acid were added at −10° C.After the reaction mixture had been stirred for 1 hour at ambienttemperature it was transferred into a separation funnel, diluted with 50ml of hexane and extracted with four 25 ml quantities of water and two25 ml quantities of brine. The organic phase was dried over sodiumsulphate and concentrated under reduced pressure. 456 mg of crudeproduct were purified by column chromatography through 8 g of silica gel(0.04–0.063 mm) with a 98:2 (v/v) mixture of hexane and ethyl acetateand afforded 139 mg (49% yield) of pure retinal (E/Z-isomeric mixture)as a viscous red oil.

EXAMPLE 18 Preparation of (all-E)-retinal-Hydroquinone Adduct

2.60 g (9.14 mmol) of (9 E/Z, 13 E/Z)-retinal (the purified product ofExample 3) and 0.514 g (4.57 mmol) of hydroquinone in 6 ml of diethylether were introduced into a 50 ml reaction flask equipped with amagnetic stirrer and argon gasification means. A trace amount, i.e.approx. 5–10 μl, of 55% aqueous iodic acid was added to the reactionmixture under argon. After about 1 hour crystallization of the formedadduct occurred, such that the flask contents consisted of anunstirrable mass of crystals. After about 16 hours under argon thecrystalline mass was supplemented with 25 ml of hexane, and theresulting suspension was stirred at room temperature for two hours. Thenthe crystals were collected by filtration, washed with hexane and driedunder high vacuum at room temperature, affording 2.27 g (84% yield) ofochre-coloured (all-E)-retinal-hydroquinone adduct with an approximateretinal: hydroquinone ratio of 8:1 (according to ¹H-NMR).

¹H-NMR (400 MHz, CDCl₃): 10.10 (doublet; J˜8 Hz, ¹H, CHO); HPLC:Constitution of retinal isomers: 3.0% (13-cis), 95.3% (all-E)(hydroquinone not included; total 98.3%).

EXAMPLE 19 Preparation of (all-E)-retinal-Hydroquinone Adduct From (9E/Z, 13 E/Z)-11,12-dihydro-11-ethoxy-retinal

In a 10 ml reaction flask equipped with a magnetic stirrer and argongasification means 992 mg (3 mmol) of (9 E/Z, 13E/Z)-11,12-dihydro-11-ethoxy-retinal were introduced into 5 ml ofmethylene chloride. After addition of a trace amount, i.e. approx. 5–10μl, of 55% aqueous hydriodic acid the reaction mixture was warmed to 40°C. for 1 hour. After this time it was established from HPLC that theethanol elimination had been completed.

The methylene chloride solvent was then removed by evaporation underreduced pressure and replaced with 1 ml of diethyl ether. 170 mg(approx. 1.5 mmol) of hydroquinone were then added and the mixture wasstirred at room temperature. Thereafter, a few crystals of the desiredadduct from a previously prepared batch were added, followed by 7 ml ofhexane, introduced slowly, into the dark solution/suspension forpromoting the crystallization. The resulting precipitate was removed byfiltration, washed with hexane and dried under high vacuum. In this waythere were obtained 348 mg (38% yield) of ochre-coloured(all-E)-retinal-hydroquinone adduct with a retinal: hydroquinone ratioof about 4:1.

Constitution of retinal isomers: 3.1% (13-cis), 95.3% (all-E) (total98.4%).

1. A process for the manufacture of retinal, of the formula

comprising reacting a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadienederivative of the general formula

or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-1,4-pentadiene derivative ofthe general formula

or a 5-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-1-pentene derivative ofthe general formula

or a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-penta-1-en-4-yne derivative ofthe general formula

or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-penta-1-en-4-yne derivative ofthe general formula

wherein R¹ signifies hydroxyl or a group OR³, R² signifies chlorine,bromine, C₁₋₆-alkoxy, C₁₋₆-alkylthio, aryloxy, aryithio,(C₁₋₆-alkyl)carbonyloxy, aroyloxy, tri(C₁₋₆-alkyl)silyloxy,di(C₁₋₆-alkyl)phosphonyloxy, (C₁₋₆-alkyl)sulphonyloxy, arylsulphonyloxy,(C₁₋₆-alkyl)sulphonyl, arylsulphonyl; di(C₁₋₆-alkyl)amino,N-aryl-(C₁₋₆-alkyl)amino or diarylamino, and R³ signifies C₁₋₆-alkyl,(C₁₋₆-alkyl)carbonyl, aroyl, (C₁₋₆-alkoxy)carbonyl,tri-(C₁₋₆-alkyl)silyl, di(C₁₋₆-alkyl)phosphonyl, diarylphosphonyl,(C₁₋₆-alkyl)sulphonyl or arylsulphonyl, with a 1,3-butadiene derivativeof the general formula

wherein R⁴ signifies C₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl ortri(C₁₋₆-alkyl)silyl, in the presence of a Lewis or Brönsted acid andsubjecting the so-obtained compound of the general formula

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIa) or

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIb) or

(starting from the 5-substituted 1-pentene derivative of the formulaIIc) or

(starting from the 5-substituted penta-1-en-4-yne derivative of theformula IId) or

(starting from the 5-substituted penta-1-en-4-yne derivative of theformula IIe) to basic or acidic conditions to eliminate therefrom themoiety R²H and thus produce, from the compound of the formula IVa,retinal of the formula I, or, from the compound of the formula IVb, thecompound of the formula

or, from the compound of the formula IVc, the compound of the formula

or, from the compound of the formula IVd, the compound of the formula

or, from the compound of the formula IVe, the compound of the formula

and, where a compound of the formula Va or Vb has been produced,hydrogenating this to produce retinal of the formula I or the compoundof the formula I′ respectively, and in each case where a compound of theformula I′ or I″ has been produced, isomerizing this under basic oracidic conditions or in the presence of a metal catalyst to the desiredretinal of the formula I.
 2. A process for the manufacture of retinal,of the formula

comprising reacting a 5-(2,6,6-trimethyl-cyclohex-1-enyl)-1,4-pentadienederivative of the general formula

or a 5-(2,6,6-trimethyl-cyclohex-2-enyl)-1,4-pentadiene derivative ofthe general formula

or a 5-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-1-pentene derivative ofthe general formula

wherein R¹ signifies hydroxyl or a group OR³, R² signifies chlorine,bromine, C₁₋₆-alkoxy, (C₁₋₆-alkylthio, aryloxy, arylthio,(C₁₋₆-alkyl)carbonyloxy, aroyloxy, tri(C₁₋₆-alkyl)silyloxy,di(C₁₋₆-alkyl)phosphonyloxy, (C₁₋₆-alkyl)sulphonyloxy, arylsulphonyloxy,(C₁₋₆-alkyl)sulphonyl, arylsulphonyl, di(C₁₋₆-alkyl)amino,N-aryl-(C₁₋₆-alkyl)amino or diarylamino, and R³ signifies hydrogen,C₁₋₆-alkyl, (C₁₋₆-alkyl) carbonyl, aroyl, (C₁₋₆-alkoxy)carbonyl,tri-(C₁₋₆-alkyl)silyl, di(C₁₋₆-alkyl)phosphonyl, diarylphosphonyl,(C₁₋₆-alkyl)sulphonyl or arylsulphonyl, with a 1,3-butadiene derivativeof the general formula

wherein R⁴ signifies C₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl ortri(C₁₋₆-alkyl)silyl, in the presence of a Lewis or Brönsted acid andsubjecting the so-obtained compound of the general formula

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIa) or

(starting from the 5-substituted 1,4-pentadiene derivative of theformula IIb) or

(starting from the 5-substituted 1-pentene derivative of the formulaIIc) to basic or acidic conditions to eliminate therefrom the moiety R²Hand thus produce retinal of the formula I, or, from the compound of theformula IVb, the compound of the formula

or, from the compound of the formula IVc, the compound of the formula,

and, where a compound of the formula I′ or I″ has been produced,isomerizing this under basic or acidic conditions or in the presence ofa metal catalyst to the desired retinal of the formula I.
 3. A processaccording to claim 1, wherein the Lewis acid is selected from the groupconsisting of zinc chloride, zinc chloride dietherate, zinc bromide,zinc di(trifluoromethanesulphonate), titanium tetrachloride, tintetrachioride, boron trifluoride etherate, iron(III) chloride,trimethylsilyl triflate and lithium perchlorate and the Brönsted acid isselected from the group consisting of p-toluenesulphonic acid,methanesulphonic acid, trifluoromethanesulphonic acid, sulphuric acidand trifluoroacetic acid.
 4. A process according to claim 3, wherein aLewis acid is selected from the group consisting of the named zincsalts, boron trifluoride etherate and iron(III) chloride.
 5. A processaccording to claim 1, wherein the Lewis or Brönsted acid is used in acatalytic amount which is 0.5 to 30 mol percent, based on the amount of5-substituted pent(adi)en(yn)e derivative of the formula IIa, IIb, IIc,IId or IIe used.
 6. A process according to claim 1, wherein 1.1 to 2.5equivalents, of 1,3-butadiene derivative of the formula III are used perequivalent of 5-substituted pent(adi)en(yn)e derivative of the formulaIIa, IIb, IIc, IId or IIe.
 7. A process according to claim 1, whereinthe 5-substituted pent(adi)en(yn)e derivative of the formula IIa, IIb,IIc, IId or IIe is reacted with the 1,3-butadiene derivative of theformula III in an organic solvent at temperatures in the range of about−70° C. to about +60° C., a lower halogenated aliphatic hydrocarbon alower aliphatic or cyclic ether; a lower aliphatic nitrile; a loweraliphatic ester; a lower aliphatic hydrocarbon; or an aromatichydrocarbon, being used as the organic solvent.
 8. A process accordingto claim 1, wherein in the elimination of the compound R²H from thecompound of the formula IVa, IVb, IVc, IVd or IVe there is used as thebase an alkali metal alcoholate, a nitrogen-containing base, atrialkylamine, or pyridine, or as the acid a strong mineral acid, or asulphonic acid.
 9. A process according to claim 1, wherein theso-produced retinal as an isomeric mixture, is isomerized to(all-E)-retinal by the acid-catalysed formation of an adduct of(all-E)-retinal with hydroquinone, said formation being effected underacid catalysis and in an organic solvent in which the adduct itself issparingly soluble, thereby affording the desired(all-E)-retinal-hydroquinone adduct in crystalline form.
 10. A processaccording to claim 9, wherein in the case where the R²H-elimination(second process step) from the compound of the formula IVa, IVb or IVcis acid-induced and the acid-catalyzed retinal-hydroquinone adductformation is intended said second process step and theretinal-hydroquinone adduct formation are combined, thus avoiding anintermediate isolation and optional purification of the retinal prior tothe adduct formation, whereby the solvent used for the acid-induced R²Helimination reaction, if not one in which the adduct would readilydissolve, is replaced on completion of the elimination reaction by onein which the adduct is insoluble or sparingly soluble, the hydroquinoneis then added and the process for formation and crystallization of the(all-E)-retinal-hydroquinone adduct is effected.
 11. A process accordingto claim 9, wherein the so obtained (all-E)-retinal-hydroquinone adductis converted to vitamin A alcohol in the predominantly (all-E)-isomericform by known methods.
 12. A 5-substituted pent(adi)en(yn)e derivativeof the general formula

wherein R¹ signifies hydroxyl or a group OR³, R² signifies chlorine,bromine, C₁₋₆-alkoxy, C₆-alkylthio, aryloxy, arylthio,(C₁₋₆-alkyl)carbonyloxy, aroyloxy, tri(C₁₋₆-alkyl)silyloxy,di(C₁₋₆-alkyl)phosphonyloxy, (C₁₋₆-alkyl)sulphonyloxy, arylsulphonyloxy,(C₁₋₆-alkyl)sulphonyl, arylsulphonyl, di(C₁₋₆-alkyl)amino,N-aryl-(C₁₋₆-alkyl)amino or diarylamino, and R³ signifies hydrogen,C₁₋₆-alkyl, (C₁₋₆-alkyl)carbonyl, aroyl, (C₁₋₆-alkoxy)carbonyl,tri-(C₁₋₆-alkyl)silyl, di(C₁₋₆-alkyl)phosphonyl, diarylphosphonyl,(C₁₋₆-alkyl)sulphonyl or arylsulphonyl, with the proviso that in thecase of the pentadiene derivatives of the formula IIa, when R¹ signifieshydroxyl, R² cannot signify arylsulphonyl.
 13. A process according toclaim 2, wherein the Lewis acid is selected from the group consisting ofzinc chloride, zinc chloride dietherate, zinc bromide, zincdi(trifluoromethanesulphonate), titanium tetrachloride, tintetrachloride, boron trifluoride etherate, iron(III) chloride,trimethylsilyl triflate and lithium perchlorate and the Brönsted acid isselected from the group consisting of p-toluenesulphonic acid,methanesulphonic acid, trifluoromethanesulphonic acid, sulphuric acidand trifluoroacetic acid.
 14. A process according to claim 13, wherein aLewis acid is selected from the group consisting of the named zincsalts, boron trifluoride etherate and iron(III) chloride.
 15. A processaccording to claim 5 wherein the wherein the Lewis or Brönsted acid isused in a catalytic amount which is 1 to 15 mol percent, based on theamount of 5-substituted pent(adi)en(yn)e derivative of the formula IIa,IIb, IIc, IId or IIe used.
 16. A process according to claim 6 wherein1.1 to 1.8 equivalents of 1,3-butadiene derivative of the formula IIIare used per equivalent of 5-substituted pent(adi)en(yn)e derivative ofthe formula IIa, IIb, IIc, IId or IIe.
 17. A process according to claim7 wherein the temperature range is from about −30° to room temperature.18. A process according to claim 7 wherein the lower halogenatedaliphatic hydrocarbon is methylene chloride or chloroform; the loweraliphatic or cyclic ether is diethyl ether, tert.butyl methyl ether ortetrahydrofuran; the lower aliphatic nitrile is acetonitrile; the loweraliphatic ester is ethyl acetate; the lower aliphatic hydrocarbon ispentane or hexane; and the aromatic hydrocarbon is toluene.
 19. Aprocess according to claim 8 wherein the alkali metal alcoholate issodium ethylate; the nitrogen-containing base is1,8-diazabicyclo[5.4.0]undec-7-ene; the trialkylamine is trimethylamineor pyridine; the strong mineral acid is hydrochloric acid, hydrobromicacid, hydriodic acid, sulphuric acid or perchloric acid; and thesulphonic acid is methanesulphonic acid, trifluoromethanesulphonic acidor p-toluenesulphonic acid.
 20. A process according to claim 10, whereinthe so obtained (all-E)-retinal-hydroquinone adduct is converted tovitamin A alcohol in the predominantly (all-E)-isomeric form by knownmethods.